Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Process for the preparation of bendamustine hydrochloride

a technology of bendamustine and hydrochloride, which is applied in the field of process for the preparation of bendamustine hydrochloride, can solve the problems of increasing the level of various process-related impurities, affecting the economic viability of the process, and difficulty in its preparation and administration

Active Publication Date: 2014-05-01
FRESENIUS KABI ONCOLOGY LTD
View PDF3 Cites 7 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent provides a process for producing Bendamustine hydrochloride with a high purity of 99.98%. The process involves the isolation and purification of the intermediate compound, which results in the removal of impurities without the need for further purification. The process is also less time-consuming and requires milder temperatures, making it more efficient and cost-effective. Overall, this patent offers a novel method for producing Bendamustine hydrochloride with improved quality and purity.

Problems solved by technology

While bendamustine has been demonstrated as efficacious, it is known to be unstable, especially in aqueous solutions, leading to formation of non-bendamustine products (i.e. “degradation impurities”) which leads to technical difficulties in its preparation and administration.
The most of the prior art processes described above involveThe use of ethylene oxide for the preparation of bendamustine hydrochloride, which is often not suitable for industrial scale processes due to difficulty in handling ethylene oxide, since it is shipped as a refrigerated liquid.Further, the known processes involve the use of strongly acidic conditions and high temperatures for the hydrolysis of ethyl ester of bendamustine and subsequent in-situ formation of bendamustine hydrochloride, thereby resulting in increased levels of various process-related impurities IMP.-A (RRT-0.46), IMP.-B (RRT-1.27) and IMP.-C(RRT-1.31) whose removal is quite difficult and make the process less economically viable.
Impurities in Bendamustine hydrochloride or any active pharmaceutical ingredient (API) are undesirable and might be harmful.
Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structural determination is not possible.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Process for the preparation of bendamustine hydrochloride
  • Process for the preparation of bendamustine hydrochloride
  • Process for the preparation of bendamustine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

reference example-1

Preparation of Bendamustine Hydrochloride as Per Patent No. DD159877

[0085]Ethyl 4-[1-methyl-5-bis-(2-hydroxyethyl)-amino-benzimidazolyl-2]butanoate (4, 4.305 g) was added to chloroform (36 mL) and agitated till clear solution is formed. The solution was cooled to 0° C. Thionyl chloride (2.175 g) was added to the above solution within 40 minutes maintaining the temperature of the solution to 0-5° C. by cooling. The reaction mixture was agitated at 0-5° C. for 1 hour. The temperature was raised slowly to room temperature by removing cooling within 2.5 to 3 hrs and subsequently agitated at room temperature for 15 to 16 hrs. The solution was dispersed by agitating in 37.5 mL concentrated hydrochloric acid whereby the excessive thionyl chloride was decomposed under increased hydrochloric acid and SO2 development. The chloroform was distilled away and further stirred for 3 hrs at around 95° C. Activated carbon (0.78 g) was added to the solution and stirred for further 30 minutes at around...

example-1

Preparation of Ethyl 4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III)

[0086]Ethyl 4-[5-amino-1-methyl-1H-benzimidazol-2-yl)butanoate (II, 40.0 g, 0.153 mol) was added to 2-bromoethanol (80 mL) and agitated for 15-30 minutes. Acetonitrile (80 mL) and calcium carbonate (61.3 g, 0.61 mol) were added to the reaction mixture. The reaction mixture was heated to 80-90° C. within 2 hours and refluxed at 80-90° C. for 34-38 hours. The reaction mixture was cooled to below 70° C. and acetonitrile (80.0 mL) was added. The reaction mixture was further cooled to 20-30° C. and filtered through celite prewashed with acetonitrile. The filtrate was concentrated at 50-60° C. under vacuum till viscous mass is obtained.

[0087]The viscous mass was cooled to 20-30° C. Dichloromethane (320.0 mL) was added to the viscous mass under stirring and washed with potassium carbonate solution (32.0 g in 200 mL water). The organic layer was washed with DM water twice. The organic layer (Di...

example-2

Preparation of Ethyl 4-{5-[bis(2-chloroethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (IV)

[0088]4-{5-[bis(2-hydroxyethyl)amino]-1-methyl-1H-benzimidazol-2-yl}butanoate (III, 90.0 g, 1.15 mole) was added to dichloromethane (6.24 L) and agitated till clear solution is formed. A solution of thionyl chloride (292.3 g, 2.52 mol) in dichloromethane (1.56 L) was added slowly in 2 to 3 hours. After complete addition of thionyl chloride solution, reaction mixture was refluxed at 35-45° C. for 6 hours. The reaction mixture was cooled to 20-30° C. and 1.95 L dichloromethane was added. Potassium carbonate solution (351.0 g in 1.95 L water) was added to the reaction mixture slowly to control the evaluation of effervescence. The layers were separated. The organic (dichloromethane) layer was washed with brine solution. The organic layer was concentrated at 30-35° C. under vacuum till viscous mass is obtained. The viscous mass was dissolved in acetone (1.95 L) and DM water (1.365 L) was slowl...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The present invention relates to an improved process for the synthesis of bendamustine, in particular, bendamustine hydrochloride of the formula (VI) and its intermediate 1-Methyl-5-[bis(2-chloroethyl)amino]-1H-benzimidazol-2-yl]lithium butanoate of formula (V), both having a purity of ≧99%, which is simple, convenient, economical, does not use hazardous chemicals and industrially viable.

Description

[0001]The present invention relates to an improved process for the preparation of bendamustine, in particular, bendamustine hydrochloride and its intermediates, both having a purity of ≧99%, which is simple, convenient, economical and industrially viable.BACKGROUND OF THE INVENTION[0002]Bendamustine hydrochloride, 4-{5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride, of the formula (VI):was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there, as the hydrochloride salt, under the trade name Cytostasan®. Since that time, it has been marketed in Germany under the trade name Ribomustin®. Bendamustine Hydrochloride as injection is available in the United States under the tradename Treanda®. Bendamustine hydrochloride is an alkylating agent that is approved for the treatment of non-Hodgkin's lymphoma, multiple myeloma and chronic lymphocytic leukemia.[0003]Bendamustine hydrochloride is a benzimidazo...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D235/16
CPCC07D235/16C07D407/04A61P35/00
Inventor MISHRA, BHUWAN BHASKARKACHHADIA, NIKUNJ SHAMBHUBHAITOMAR, VINOD SINGHLAHIRI, SASWATA
Owner FRESENIUS KABI ONCOLOGY LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com